The chemical transformations needed for production and analysis of radioactive medical materials are preferably done using automated modules. These modules provide for automatic handling of radioactive materials in a reproducible manner, thus reducing personnel exposure to radiation and improving reliability of production and analysis.
In known chemical synthesis/analysis systems, materials such as liquids and gases are transferred from one location to another via valves and tubes (also referred to as “plumbing”, network of channels, lines) and require a “motive force” (e.g., provided by vacuum, pumping or the like). The plumbing can be installed at the time of the system manufacturing and only replaced during regular maintenance (“permanent” or “cleanable” plumbing), or it can be incorporated into a cartridge meant to be used only for one production/analysis run (disposable plumbing). Initially, this basic feature greatly simplified the design of the machines and allowed fast introduction of these systems in response to growing production of PET and SPECT radiopharmaceuticals. However, several decades in the field practice revealed a number of drawbacks typical for these systems.
In many cases, transfer of the liquid material results in considerable losses of the liquid material in the tubes due to large quantities of small droplets left on the inner walls of the lines (tubes) (which is inevitable because of high surface-to-volume ratio of the tubes). This is a fundamental limitation precluding handling of small quantities of liquid. Synthesis of the radiopharmaceuticals is therefore limited to relatively diluted solutions, as milliliter scale volumes of solvents are needed for complete transfer of a certain amount of reagent. Analytical systems relying on the network of tubes for distribution of the samples have to use no less than hundreds of microliters of samples for reliable and quantitative transfer.
Additionally, lines and/or valves may clog, be pinched or leak. These operational problems are very hard to detect, as it is nearly impossible to inspect every inch of a complex plumbing.
Compared to conventional wet chemistry done in the flasks and beakers, such automated modules provide very little flexibility for chemists. The fixed plumbing schematic of the tubing-based instruments implies that all functions of the machine must be defined at the design stage. However, introduction of new tasks, or improvement of existing methods, often require changes in the fluid schematic. These changes may require (trigger) changes in the hardware, electrical and electronic components as well as in the software operating the module. Attempts to improve functionality have inevitably led to complicated schemes, as all functionality should be in place, whether it is needed or not for each particular synthesis. To perform new operations, the instrument has to be re-designed or modified. Therefore, most of the existing radiochemistry modules can only perform a limited number of predefined operations; i.e., they are not flexible.
The limited operational flexibility of these machines also allows little chance to recover after an error. Currently, if one operation within a run is not performed as expected, the entire run has to be abandoned and the machine has to be reinitialized either through, for example, a clean cycle or by inserting a new cassette. That is because all operations have to be envisioned prior to the start of the run, even more often they have to be integrated into the machine design. More so, most machines can only execute tasks in a pre-defined sequence with no options to repeat or skip steps or to change their order. As a result, current machines have only one chance to complete their task, with no option to recover from minor errors, such as incomplete liquid delivery.
Furthermore, instruments, which rely on plumbing and valves, require complex cleaning procedures after each transfer in order to prevent contaminants in the subsequent procedure. In the case of systems based on permanent plumbing, a complex cleaning/drying cycle is performed after each run to ensure that no contaminants are left in the lines and extensive cleaning validations are required. This problem was mitigated by the use of disposable cassettes where a new set of lines is used for each run. However, some lines in the cassette are often used for several consecutive transfers and the operation protocol has to incorporate interim cleaning steps.
A separate set of limitations of current radiochemistry machines is related to the measuring of fractions of a sample or reagent stock solution. The most common mode of transfer is the transfer of the entire volume of material premeasured in a container. Alternatively, a separate system of measuring out a fraction of the container content is constructed. Such system normally requires an excess of material to be transferred. For instance, if one milliliter of a solution needs to be transferred out of a 5 milliliter vial, some amount of this solution will inevitably be wasted to prime the lines coming in and out of the vial, the measuring device (syringe) and, potentially to wash the lines prior to transfer.
A large number of systems for radio-synthesis and/or analysis of radiopharmaceuticals have been reported and patented, which rely on plumbing and valves to route liquids. Those using disposable cassettes still contain plumbing (although disposable) and valves and movable components as well as a rigid inflexible schematic. In this case the complexity is increased by the mechanical interface between the valves and their actuators, and the electronic and liquid connections between the disposable and the permanent parts of the system.